Safety and Effectiveness Study of Pre-operative Artesunate in Stage II/ III Colorectal Cancer

Phase 2Not Yet RecruitingNCT07095309

Metanoic Health Ltd.120 enrolled

Overview

TThis study evaluates the safety and effectiveness of pre-operative artesunate, given orally once a day for 14 days prior to surgery, in patients with Stage II/III colorectal cancer. Artesunate is an established antimalarial drug with an excellent safety profile. It is well tolerated, affordable, and widely available. Several laboratory studies and one small pilot clinical study in patients with colorectal cancer have shown that artesunate can reduce the proliferation and growth of cancer cells. One hundred patients diagnosed with Stage II/III operable colorectal cancer will be randomly allocated to receive oral artesunate 200 mg daily or a matching placebo for 14 days prior to surgery. Patients will then be followed closely for 5 years to determine whether pre-operative artesunate reduces the risk of cancer recurrence after surgery.

Artesunate is an established antimalarial drug belonging to the artemisinin class of drugs, has an excellent safety profile, is well tolerated and affordable. In last two decades, artemisinins have shown potent and broad anticancer properties in a range of cell lines and animal models, supporting the hypothesis that artemisinins have the potential to be an effective anti-cancer therapy. Multiple potential mechanisms of action include anti-proliferative effects through cell-cycle disruption, reactive oxygen species (ROS) -induced DNA damage, induction of apoptosis, anti-angiogenesis, immunomodulation and induced radiosensitivity. Despite a multi-modality treatment approach to colorectal cancer, 5 year overall survival does not currently exceed 60%. Neoadjuvant pre-operative therapy may be more effective at eradicating micrometastases compared to adjuvant therapy delivered following the delay and immunological stress of surgery. However current neoadjuvant chemotherapy regimens are often associated with significant side effects and may result in a delay in surgery whilst patients recover. A well tolerated, affordable, novel anticancer agent that could be given to patients whilst they wait for surgery, without causing a surgical delay due to treatment related toxicity, would have a significant clinical impact on patient care. The NeoART trial is a phase II multicentre randomised, double blind, placebo controlled trial (RCT) for patients undergoing primary surgery for Stage II/III colorectal cancers. Patients are randomised (1:1 ratio) to receive either a two week course of neoadjuvant artesunate 200mg once daily or matching placebo. Both patients and health care professionals are blinded to treatment allocation arm to minimise outcome-reporting bias. The primary endpoint of the trial is recurrence free survival two years after surgery. Secondary endpoints include 2 and 5 year overall survival, treatment related toxicity, tolerability and patient quality of life. A translational sub-study looking at predictive and prognostic biomarkers is also planned.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Aged 18 or over * Histologically proven single primary site colorectal adenocarcinoma or high grade dysplasia plus unequivocal radiological evidence of invasive cancer * Stage II/III colorectal cancer planned for surgical resection and no clinical indication for neoadjuvant preoperative chemotherapy/chemoradiation therapy * WHO performance status 0,1 or 2 * Adequate full blood count: White Cell Count (WCC) \>3.0 x 109 /l; Platelets \>100 x 109/l; Haemoglobin (Hb) \>80g/L * Adequate renal function : Glomerular Filtration Rate \>30ml/min by Cockcroft-Gault formula. * Adequate hepatobiliary function : Total bilirubin \< 3 x Upper limit norm * Female participants of childbearing potential must have a negative pregnancy test \<72 hours prior to initiating study intervention and agree to avoid pregnancy using adequate, medically approved contraceptive precautions for up to 6 weeks after the last dose of study treatment interventions. * Male participants with a partner of childbearing potential must agree to use adequate, medically approved contraceptive precautions during and for up to 6 weeks after the last dose of the study treatment intervention. * Patient able and willing to provide written, informed consent for the study. Exclusion Criteria: * Contraindication to use of artesunate due to hypersensitivity * Pregnancy or lactation * Male or female participants unwilling to use an effective method of birth control (either hormonal in the form of the contraceptive pill or barrier method of birth control accompanied by the use of a proprietary spermicidal foam/gel or film) ; or agreement of true abstinence from time consent is signed until 6 weeks after the last dose of study treatment intervention (i.e. withdrawal, calendar, ovulation, symptothermal and post ovulation are not acceptable methods) * History of hearing or balance problems * History of immunosuppression * Patient weight \< 52 kg or \> 110 kg * Other planned intervention, apart from standard of care * Any other malignant disease diagnosis within the preceding 2 years with the exception of non-melanomatous skin cancer and carcinoma in situ * Lactose intolerance

Locations (6)

Hospital Sultanah Bahiyah

Alor Star, Kedah, Malaysia

Hospital Kuala Lumpur

Kuala Lumpur, Kuala Lumpur, Malaysia

Pusat Perubatan Universiti Malaya

Kuala Lumpur, Kuala Lumpur, Malaysia

Hospital Umum Sarawak

Kuching, Sarawak, Malaysia

Hospital Sungai Buloh

Sungai Buloh, Selangor, Malaysia

Hospital Pulau Pinang

Pulau Pinang, Malaysia

Outcomes

Primary Outcomes

Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation

RFS is defined as the time from randomisation to the first documented recurrence of colorectal cancer (local or distant) or death from any cause, whichever occurs first. Recurrence will be assessed using standard CT scans of the chest, abdomen, and pelvis, clinical examination and measuring carcinoembryonic antigen (CEA). Confirmation of recurrence may include histological evidence where clinically indicated. Unit of Measure: Months

Time frame: 2 years following study randomisation.

Secondary Outcomes

Recurrence-Free Survival at 5 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation

RFS is defined as the time from randomisation to the first documented recurrence of colorectal cancer (local or distant) or death from any cause, whichever occurs first. Recurrence will be assessed using standard CT scans of the chest, abdomen, and pelvis, clinical examination and CEA . Histological confirmation of recurrence will be obtained where clinically indicated. Unit of Measure: Months

Time frame: 5 years from study randomisation

Overall Survival (OS) at 2 and 5 Years Post-Randomisation

Survival status will be determined through clinical follow-up, hospital records, and national death registries where available. Unit of Measure: Months

Time frame: 2 years and 5 years following study randomisation.

Colon Cancer-Specific Mortality at 2 and 5 Years Post-Randomisation

Time frame: 2 years and 5 years following study randomisation.

Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0

The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one artesunate-related adverse event, by CTCAE grade.

Time frame: Assessment at Day 7 following initiation of study intervention (artesunate or matching placebo).

Incidence of Artesunate-Related Toxicity Assessed by Common Terminology CTCAE v5.0

The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Causality will be assessed by the site investigator and confirmed by the clinical trial safety team. Adverse events will be coded and reported by type and severity.

Time frame: Assessment at Day 14 following initiation of study intervention (artesunate or matching placebo).

Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0

The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the CTCAE. Causality will be assessed by the site investigator and confirmed by the clinical trial safety team. Adverse events will be coded and reported by type and severity. Unit of Measure: Number of participants with at least one artesunate-related adverse event, by CTCAE grade.

Time frame: Assessment at Day 42 following initiation of study intervention (artesunate or matching placebo).

Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0

The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade.

Time frame: Assessment at Day 7 following administration of study intervention (artesunate or matching placebo).

Incidence Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Day 14

Time frame: Assessment at Day 14 following study intervention

Incidence of adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0

Time frame: Assessment at Day 42 following study intervention

Pathological assessment of tumour regression post intervention

Tumour regression will be assessed by histopathological examination of the surgical resection specimen. The assessment will include: * Degree of tumour regression in the primary tumour bed * Presence of tumour involvement at the resection margins * Evidence of tumour invasion into the serosa (pT4a) and lymph node involvement (number and proportion of positive lymph nodes). * Histopathological evaluation Unit of Measure: Number and proportion of participants with positive lymph nodes, serosal involvement, and positive resection margins.

Time frame: Post surgical pathology review (following Day 14 of study intervention)

Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline

Quality of life will be assessed using validated, self-administered questionnaires: 1. EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) 2. EORTC QLQ-CR29 (Colorectal Cancer-Specific Module) These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires.

Time frame: Assessment at Day 1 of study intervention (baseline assessment)

Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires

Time frame: Assessment at Day 7 of study intervention

Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires post intervention

Time frame: Assessment at Day 14 of study intervention

Incidence of Surgery-Related Adverse Events Assessed by CTCAE v5.0

The number and proportion of participants experiencing surgery-related adverse events (AEs) will be recorded. Events will be graded using the CTCAE version 5.0, with severity classified from Grade 1 (mild) to Grade 5 (death related to AE). Events of interest include, but are not limited to, surgical site infection, anastomotic leak, wound dehiscence, postoperative bleeding, and thromboembolic events. Unit of Measure: Number of participants with at least one surgery-related AE, categorised by CTCAE grade.

Time frame: From time of surgery up to 3 months post surgery

Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy

Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL)

Time frame: Day 1 of study intervention (baseline assessment).

Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy

Time frame: Assessment at Day 7 of study intervention

Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy

Time frame: Assessment at Day 14 of study intervention

Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy

Time frame: Assessment at Day 42 of study intervention

Immunohistochemical analyses of paraffin-embedded tumour sections to assess Kirsten rat sarcoma viral oncogene homolog (Kras) mutation status

KRAS mutation status will be assessed in tumour tissue sections obtained from pre-intervention (diagnostic biopsy, Day 0) and post-intervention (surgical resection, Day 15) samples. Immunohistochemistry (IHC) will be performed. Comparisons will be made to evaluate changes in mutation status and association with response to artesunate therapy. Unit of Measure: Number and proportion (%) of participants with KRAS mutant tumours at each time point.